The incidence of testicular germ cell carcinoma (TGCC), the most common malignancy developing in young men, has increased several-fold since the 1950s. The etiology of TGCC is obscure and our knowledge of risk factors is limited largely to demographic characteristics, family history, and a history of undescended testes. Clinical, non-human experimental and epidemiologic studies of TGCC provide evidence that exposure to abnormal levels of estrogens and/or androgens, either in utero, perinatally, and/or early in life, may be a key etiologic factor for TGCC. During the past 4.5 years, we have conducted a combined population-based case-control and case-parent triad study to begin to test, using molecular genetic methods, the hypotheses that TGCC risk is associated with 1) variation in a man's genes controlling testosterone synthesis, metabolism, and signaling; and 2) maternal variation in genes her hormonal milieu in early pregnancy (as a surrogate for in utero exposure), when fetal tissue is most susceptible to damage. Cases (n=285 expected), controls (n=747 expected), and parents of cases (n=187 case-parent sets expected) are being ascertained and recruited from among metropolitan Seattle-Puget Sound residents. Cases and controls have been interviewed in-person, and parents via telephone, regarding medical and lifestyle histories. DNA samples have been obtained from nearly every participant and assayed for candidate polymorphisms (4 loci in the case-control study only, 8 loci in case-parent triad study only, and 7 loci in both designs). We propose to continue both the case-control and case-parent components to test our initial specific aims with increased rigor by doubling our sample size, and by including a more comprehensive set of candidate genes and polymorphisms within each gene. In addition, we propose two new specific aims that extend the test of the "steroid hormone" hypothesis: that TGCC risk is related to variation in a man's genes coding for: 1) cytokines (and their receptors) that influence testicular steroidogenesis, and 2) base-excision repair proteins that protect against oxidative DNA damage resulting from reactive estrogen metabolites. Continuing our study will allow us to address our specific aims with a total of 570 incident. TGCC cases, 1,514 demographically similar controls, and 714 parents (yielding about 375 case-parent sets). We will determine genotypes for approximately 420 hundred loci per individual and use multilocus analysis methods to assess overall associations and gene-gene interactions. The findings from this study will add new information regarding the epidemiology and etiology of TGCC, and will serve as a resource for future investigations of the interplay of genetic and non-genetic factors in these malignancies.